Sepsis is a significant health problem in the United States with an estimated nearly 750,000 new cases annually [1]. Sepsis is the 11th leading cause of death and the leading cause of mortality in the non-coronary intensive care unit with a mortality rate of 30-50% [1-3]. The frequency of sepsis has increased over 135% in a ten-year interval and is predicted to continue to rise with the increase in antibiotic resistance [1, 4]. In addition to the fully developed cases of sepsis, there are millions of patients on an annual basis in the U.S. alone that suffer severe infection or the clinical manifestations similar to sepsis that require diagnostic evaluation. Ironically, although treatment of sepsis has evolved in the last decades with newer therapeutic options of improved antibiotics and more novel approaches, such as inhibitors of the inflammatory response, little has changed to improve diagnosis and therapeutic monitoring [1-8]. Yet the medical detection and confirmation of patients suffering from infections or sepsis requires laboratory blood tests.
The laboratory diagnosis of infection and sepsis still relies on the same basic modalities that have been available since the 1970s or before. Clinical decisions regarding the likelihood of infection or sepsis are typically made on leukocyte counts, the presence of myeloid immature forms in the peripheral blood (bands or “left-shift”), laboratory tests for “acute phase reactants”, such as C reactive protein, and clinical findings, such as fever. The cellular diagnostic parameters are typically problematic and lack specificity, particularly in infants [9, 10] and the elderly [11]. Furthermore, recent evidence indicates that leukocyte counts may have no significant influence on clinical decisions in patients with abdominal pain regarding surgery [12] and band counts provide little or no diagnostic information as to the probability of infection in a given patient [13, 14]. C reactive protein (CRP) levels, although not a new diagnostic test, have increasingly been advocated as a more objective diagnostic assay and therapeutic monitor, particularly in the neonatal and elderly population [15-19]. The advantages of CRP values, such as lack of interpretative subjectivity and improved sensitivity and specificity, are most evident in patient populations where studies have demonstrated a poor diagnostic utility of leukocyte counts and immaturity indices, such as in neonates, the elderly, and immuno-compromised patients. However, reliance on CRP values for sepsis or infection detection is also problematic in patients with co-morbid disease process. Being one of many acute phase reactants, CRP becomes elevated in any disease process with tissue injury, not just infection [16, 18, 20, 21]. Another limitation of CRP is a lack of specificity in distinguishing viral from bacterial infection. This lack of specificity as to the etiology of an infectious process has lead to the recent advocacy by some for the diagnostic utility of procalcitonin (PCT) measurements as a more specific indicator of bacterial infection [22-24]. Similarly there has been enthusiasm in the last ten years for potential diagnostic utility of cytokine levels, such as IL-6, and tumor necrosis factor (TNF) levels in septic patients [25-31]. But such studies generally have failed to demonstrate significant diagnostic utility for such tests and they additionally proved problematic due to the short half-life and sample stability of such inflammatory mediators. Molecular diagnostics have also made promises of newer approaches for early detection or prognosis, but still have fallen short due to technical limitation in turn around time, sensitivity, or cost [32, 33]. PCT, cytokines, TNF, and other molecular diagnostics currently remain experimental and none has been FDA cleared for in vitro diagnostic use to date.
The optimal diagnostic for sepsis and severe infection should be directed to early and specific changes related to the systemic acute inflammatory response. One of the major problems with the current laboratory tests for detecting the acute inflammatory response related to infection or tissue damage is the lack of specificity [14].